The cis-[PtCl2(naza)2] complexes (1-3) containing monosubstituted 7-azaindole halogeno-derivatives (naza), showed significantly higher activity than cisplatin towards ovarian carcinoma A2780, its cisplatin-resistant variant A2780R, osteosarcoma HOS, breast carcinoma MCF7 and cervix carcinoma HeLa cell lines, with the IC50 values of 3.8, 3.5, 4.5, 2.7, and 9.2 μM, respectively, obtained for the most active complex 3. As for 4 and 5 having disubstituted 7-azaindoles in their molecule, the significant cytotoxicity was detected only for 4 against A2780 (IC50 = 4.8 μM), A2780R (IC50 = 3.8 μM) and HOS (IC50 = 4.3 μM), while 5 was evaluated as having only moderate antiproliferative effect against the mentioned cancer cell lines with IC50 = 33.4, 24.7 and 46.7 μM, respectively. All the studied complexes 1-5 effectively avoided the acquired resistance of ovarian carcinoma cell line. On the other hand, the complexes did not reveal any inhibition activity on the purified 20S proteasome from the A2780 cells. The representative complexes 3 and 5 showed low ability to be hydrolysed, but their stability was markedly lowered in the presence of physiological sulphur-containing biomolecule glutathione (GSH), as proved by the 1H NMR spectroscopy and mass spectrometry studies. A rate of interaction of the studied complexes with GSH was affected by an addition of another mechanistically relevant biomolecule guanosine monophosphate. The differences in interactions of 3 and 5 with GSH correlate well with their different cytotoxicity profiles.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Cisplatin chemistry   pharmacology   MeSH
• Glutathione chemistry   MeSH
• HeLa Cells MeSH
• Mass Spectrometry MeSH
• Indoles chemistry   pharmacology   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Molecular Structure MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• Organoplatinum Compounds chemistry   pharmacology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-azaindole dimer MeSH Browser
• Cisplatin MeSH
• Glutathione MeSH
• Indoles MeSH
• Organoplatinum Compounds MeSH
• Antineoplastic Agents MeSH

A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) was prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.

• MeSH
• Ditiocarb analogs & derivatives   chemistry   pharmacology   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Proteasome Inhibitors * MeSH
• Humans MeSH
• Copper MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms enzymology   pathology   MeSH
• Nickel MeSH
• Organometallic Compounds chemistry   pharmacology   MeSH
• Proteasome Endopeptidase Complex metabolism   MeSH
• Zinc MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• bis(N,N-diethyldithiocarbamate)Cu (II) complex MeSH Browser
• Ditiocarb MeSH
• Enzyme Inhibitors MeSH
• Proteasome Inhibitors * MeSH
• Copper MeSH
• Nickel MeSH
• Organometallic Compounds MeSH
• Proteasome Endopeptidase Complex MeSH
• Zinc MeSH